CD1 molecules are evolutionarily conserved molecules from the immunoglobulin superfamily present in all mammalian species. Distinct from both MHC class I and MHC class II molecules, the CD1 family comprises a third group of MHC-like molecules with diverse functions in both antigen specific and systemic immune responses. CD1 molecules are grouped according to sequence homology into two primary groups: Group one containing human CD1a, b, c and Group two containing human CD1d and mouse Cd1.1 and CD1.2. Unlike MHC class I and II molecules which present peptides to T lymphocytes, CD1 (b and c) has been shown to present lipid glycolipid antigens from Mycobacteria, thus expanding the realm of potential immunogens. CD1 present in mice has been definitively connected to the function of NK1+T cells, which following activation promptly secrete cytokines which can influence the overall dynamics of immune response in both infections and autoimmunity. Additional information is required to understand this complex system which intertwines antigen specific and innate immunity. This proposal addresses three main aspects of the CD1 dependent immune response in mice, with an additional aim designed to expand this information to understanding human Cd1d, of which little is currently known. To understand the role of CD1 in controlling the overall immune system balance and its disruption in autoimmunity, we will utilize CD1 deficient animals and genetic models of diabetes (NOD mice) and lupus (MRL-lpr/lpr mice) in order to analyze the mechanisms of autoimmune suppression. Secondly, we seek to understand the effects of this general immune control on infectious disease, and to determine relative effects of cytokine balance and specialized antigen presentation in mouse models of tuberculosis, leishmaniasis, and helminthic infection. A third aim is to reveal the physiological range of antigen specific responses involving CD1, through development of T cells specific for both alloantigens and infectious microbes. Finally, we have generated human CD1d transgenic mice to determine if these molecules can function similarly to human Cd1b and c and/or mouse CD1. Introducing the human CD1d transgene into CD1-deficient mice will allow testing for whether the mouse and human molecules are functionally homologous in the control of NK1+ T cell development and cytokine secretion. The flexibility of analyzing the human molecule in the mouse system will allow dissection of the potential importance of human CD1d in a number of diseases where cytokine balance and specialized antigen presentation affect pathology.